Amino-substituted purine derivatives



Unified tes atent No Drawing. Filed July 1, 1959, Ser. No. 824,172 9Claims. (Cl. 260-2475) This invention relates to amino-substitutedpurine derivatives and more particularly to compounds having thetautomeric structural formulas R is hydrogen, an alkyl or substitutedalkyl radical,

an aralkyl or substituted aralkyl radical, or an aryl or substitutedaryl radical, one of substituents R R and R is a nitrogen atom which isa member of a heterocyclic ring comprising a 4-, 5- or 6-memberedmethylene chain which may be substituted by lower alkyl, lower alkoxy orhalogene and which may be interrupted by a further heteroatom, such asnitrogen or oxygen, one other of substituents R R and R is a substitutedamino radical, a hydrazine or substituted hydrazino I radical, a guanidoor substituted guanido radical, or a nitrogen atom which is a member ofa heterocyclic ring comprising a 4-, 5- or 6-membered methylene chainwhich may be substituted by lower alkyl, lower alkoxy or halogene andwhich may be interrupted by a further heteroatom, such as nitrogen oroxygen, the third of substituents R R and R is hydrogen, halogen, ahydroxyl or substituted hydroxyl radical, a mercapto orsubstituted-mercapto radical, an amino or substituted amino radical, avhydrazino or substituted "hydrazino. radical, a guanido or substitutedguanido radical, or. a nitrogen atom which is a member of a heterocyclicring comprising a 4-, 5- or 6-membered methylene chain which may besubstituted by lower alkyl, lower alkoxy or halogene and which may beinterrupted by a further heteroatom, such as nitrogen or oxygen, and 9 Rin addition may be an alkyl or substituted alkyl radical, an aralkyl orsubstituted aralkyl radical, or an aryl or substituted aryl radical,

a 1 i e (in 3,016,378 Patented Jan. 9, 1962 Z2 t I t Z N NJ-Z3 it (IV)wherein:

R has the meanings previously defined in connection with Formulas I andII, I i

one of substituents Z Z and Z is a halogen atom,

one other of substituents Z Z and Z is a substituted amino radical, ahydrazine or substituted hydrazino radical, a guanido or substitutedguanido radical, a halogen atom, or a nitrogen atom which is a member ofa heterocyclic ring comprising a 4-, 5- or 6-membered methylene chainwhich may be substituted by lower alkyl, lower alkoxy or halogene andwhich may be interrupted by a further heteroatom, such as nitrogen oroxygen, and

the third of substituents Z Z and Z is hydrogen, a

halogen atom, a hydroxyl or substituted hydroxyl radical, a mercapto orsubstituted mercapto radical, an amino or substituted amino radical, ahydrazino or substituted hydrazine radical, or a nitrogen atom which isa member of a heterocyclic ringv comprising a 4-, 5.- or 6-memberedmethylene chain which may be substituted by lower alkyl, lower alkoxy orhalogene and which may be interrupted by a further heteroatom, such asnitrogen or oxygen, and R in addition may be an alkyl or substitutedalkyl radical, an aralkyl or substituted aralkyl radical, or an aryl orsubstituted aryl radical v v with a compound of the formula wherein R isa nitrogen atom which is a member of a heterocyclic ring comprising a4-, 5- or 6-membered methylene chain which may be substituted by loweralkyl, lower alkoxy or halogene and which maybe interrupted by a furtherheteroatom, such as nitrogen or oxygen, in the presence of ahydrogenhalidencutralizing compound at atemperature between-'20 and +250 C. I

ln'those iustances'where the halogenated purine used as the startingmaterial, i.e. a compound of the formulas III' or IV above, also has asa substituent at least one nitrogen atom which is a meniber of ahcterocyclic ring comprising a 4-, 5- or 6-membered methylene chainwhich may be substituted by lower alkyl, lower alkoxy or halogene andwhich may be interrupted by a further heteroatom, such as nitrogen oroxygen, R in Compound V may also be a substituted amino radical,-ahydrazino or substituted hydrazine radical, or a guanido or substitutedguanido' radical. lnthose instances where the halogenated purinereaction component contains as one substituent a nitrogenatom which is amember of a heterocyclic ring comprising a 4 5- or 6-membered methylenechain which may be substituted by lower alkyl, lower alkoxy or halogeneand which may be interrupted by a hy'droxyl or substituted mercaptoradical.

further hetero atom, such as nitrogen or oxygen, and as anothersubstituent a substituted amino radical the substituent of which in turnincludes a nitrogen atom which is a member of a heterocyclic rincomprising a methyl- I Thus, one or more of the halogen atoms of thehalogenated purine are exchanged for the heterocyclic radical R,accompanied by the formation of a hydrogen halide which is tied up bythe hydrogen halide-neutralizing compound present in the reactionmixture.

Typical examples of halogenated purines of the Formulas III and IV whichmay be used as starting materials in the preparation of the purinederivatives according to the present invention are the following:

Illustrative examples of suitable compounds of the Formula V which maybe used in the preparation of the purine derivatives according to thepresent invention are the following: Alcohols, phenols, primary andsecondary amines, heterocyclic amines such as morpholine, piperidine,pyrrolidine or piperazine, which may be substituted with lower alkyl,lower alkoxy or halogene, guanidines, hydrazines,dialkylaminoalkylamines, amino alcohols,

- mercaptans, thiocarboxylic acids and thiophenols.

As previously indicated, it is advantageousto perform the reactionbetween the halogenated purine III or IV and the Compound V in thepresence of an acid-binding agent, and specifically in the presence of acompound capable of tying up or neutralizing the hydrogen halide formedby the reaction. Typical examples of suitable such acid-binding agentsare alkali metal hydroxides, alkali metal carbonates, alkali metalalcoholates and tertiary amines. If the reactioncomponent of the formulaH-R (V) is itself capable of acting as an acidbinding agent, it may beprovided in excess over the amount stochiometrically required to bringabout the desired substitution of the halogen atom or atoms in thehalogenated purine reactant. Under such conditions the excess thenfunctions as the necessary acid-binding component of the reactionmixture.

The reaction between the halogenated purine and the Compound V may becarried out in the presence of solvents or diluents, preferably inert.However, the presence of such diluents or solvents is not essential tothe reaction. Examples of suitable inert solvents are acetone, dioxan,benzene, dimethyl-formamide and the like.

The optimum reaction temperature within the range of 20 and 0 C. varieswith the reaction components but can readily be determined by a simplepreliminary test run. In those instances where the reaction mixtureincludes a diluent or solvent and the boiling point of the mixture isnot high enough to reach the previously determined optimum reactiontemperature at atmospheric pressure, the reaction may be carried out atsuper atmospheric pressure sufliciently elevated to raise the boilingpoint of the reaction mixture to the optimum reaction tempera ture;

If the reaction mixture does not contain alkalies and the optimumreaction temperature-is sufiiciently low, water and alcohols may beemployed at the diluent or solvent medium because, for all practicalpurposes, they do not react with the halogenated purines under such mildconditions.

Finally, if the reactant H-R (V) is a liquid under the optimum reactionconditions itmay itself serve as the diluent or solvent medium, in whichcase it is provided in the reaction mixture in sufficient excess overthe amount stochiometrically required to bring about the displacement ofthe desired number of halogens in the. halogenated purine (III or IV) bythe radicalR. If the halogenated purine starting material is one whereintwo or all three of substituents Z Z and Z are halogen atoms, theexchange of one, two or all three halogens for the radical R of CompoundV may be accomplished stepwise. More particularly, we have found that atlow or moderately elevated temperatures only one or two of the halogenatoms in the purine starting material are replaced by radical R, whereasconsiderably higher temperatures within the above-indicated operativerange are required .to replace all three of the halogen atoms if thepurine starting material is a tri-halo-substituted purine. For example,by reacting 2,6,8-trichloro-7-rnethyl-purine with morpholine in thepresence of dioxan or dimethylformamide as a solvent medium whilecooling the reaction mixture so that the temperature does not rise above5 C. only one chlorine atom, most probably that in the 8-position, isreplaced by a morpholyl radical. On the other hand, if the samereactants are heated slightly in the presence of dioxan as a solvent twochlorine atoms,

probably those in the 6- and 8-positions, are replaced by morpholylradicals. Finally, if 2,6,8-trichloro-7-methylpurine is refluxed for onehalf hour with an excess of morpholine at the boiling point ofthe'mixture, the excess of morpholine serving as the solvent medium inthis case, all three of the chlorine atoms in the trichlorosubstitutedpurine are replaced by morpholyl radicals and the reaction product is2,6,8-trimorpholyl-7-methylpurine.

We have further found that the halogen atoms in the halo-substitutedpurine starting materials can be surprisingly easily replaced byheterocyclic amino radicals, such as morpholyl, piperidyl, piperazino orpyrrolidyl radicals, which may be substituted by lower alkyl, loweralkoxy or halogene, with the aid of the method described herein. Toillustrate, the preparation of 2-(7- diethylamino-propylamino)-6diethylamino 7 methylpurine requires very vigorous reaction conditions;a mixture of 2-chloro-6-diethylamino-7-methyl-purine and'y-diethylamino-propylamine must be heated for 17 hours at C. underpressure (see J.A.C.S., Vol. 67 (1945), page 1271). In contrast thereto,the preparation of 2,6,8- tripiperidyl-7-methyl-purine from2,6,8-trichloro-7-methylpurine and piperidine according to the presentinvention merely requires refluxing the reaction mixture for two hoursat its boiling point (about 106 C.).

The reaction for the preparation of the amino-substituted purinederivatives according to the present invention may also be performed inthe presence of reaction accelerators, among which copper, copper saltsand potassium iodide have been foundto be particularly suitable.

The following examples will further illustrate the present invention andenable others to understand it more completely. It will be understood,however, that the invention is not limited to the particular examplesgiven below.

I I EXAMPLE 1 Preparation of various 2-chl0r0-6,8-aiamin0-7-methylpurine derivatives from 2,6,8-trichloroJ-methyl purine and thecorresponding amino compounds (0.) 2-CHLORO G,S-DIPIPERIDYIrI-METHYLPURINE poured into about 350 cc. water, whereby the purine hydrochlorideredissolved and an initially greasy precipitate formed which, however,soon solidified. The precipitate was filtered off on a vacuum filter,the filter cake was washed and then dried at room temperature. 10.2 gm,

acne-37s that is-76% of theory, of a compound having the structuralformula N CH3 r': d r

were obtained. For purposes of purification, the raw compound Wasrecrystallized once from methanol, whereupon it was obtained in the formof colorless, brilliant, elongated leaflets having a melting point of140 to 142 C.

(b) Z-CHLORO-6,8-DIMORPHOLYL-7-METHYL PURINE By following a procedureanalogous to that described under (a) above, but using instead ofpiperidine an equivalent amount of morproline, a compound having thestructural formula was obtained with a yield of 75% of theory. Uponreprecipitation of the raw product from hot 0.5 N hydrochloric acid, thepurified product was obtained in the form of an ivory micro-crystallinepowder having a melting point of 284 to 286 C. V 7

EXAMPLE 2 Preparation of various 2-chZora-6,8-diamin0-7-methyl purinederivatives from 2,6-dichlor0-8-amin0-7-methyl purines and thecorresponding amines (a) 2-CHLORO-G-MORPHOLYL-B-BENZYLAMINO-7- METHYLPURINE A mixture of 3.1 gm. (0.01 mol)2,6-dichloro-8-benzylamino-7-methy1 purine, having a melting point of226 to 228 C. and 5 cc. morpholine, dissolved in 30 cc. dimethyiforrnamide, was heated for 1 hour at about 125 C. The reaction solutionthus obtained was then poured into 150 cc. Water, whereby an initiallygreasy precipitate formed which solidified after being'allowed to standfor a short period of time. The precipitate was separated by vacuumfiltration, washed and dried. 3.1 gm., that is 86% of theory, of acompound having the structural formula were obtained. Uponrecrystallization of the raw product from methanol, the purified productwas obtained in the form of virtually colorless, brilliant needleshaving a meltpint of 211 to 213 C.

(b) Z-CHLORO-G-HYDRAZINO-$-MORPHOLYL-7-METHYL 'PURINE By following aprocedure analogous to that described under (a) above, but using insteadof morpholine and 2,6-dichloro-8-benzylamino-7-methyl purine anequivalent 6 amount of hydrazine. and 2,6-dichloro-8-morpholyl-7- methylpurine, a compound having the structural formula was obtained with ayield of 57% of theory. Upon reprecipitation from cold, approximatelyOAN hydrochloric acid, the product was obtained in the form of a lightgray, microcrystallinepowder which decomposed around 250 C. (d)2-CHLORO-6-(*y-METHOXY-PROPYLAMINO)-8- PIPERIDYL-7-METHYLIPURINE Byfollowing a procedure analogous to that described under (0) above, butusing instead of hydrazine, an equivalent amount of'y-hydroXy-propylamine, a compound having the structural formula l nu0H3 v Gil EE was obtained with a yield of 81% of theory. Upon i e-rprecipitation from cold, 0.1 N hydrochloric acid, the purified productWas obtained in the form of virtually colorless, microcrystallineneedles having'a melting point of l14t o 116C. (e)2-CHLOR0-6-GUANIDO-8-PIPEitIDYL-7-METHYL v PURINE Byfollowinga-procedure 'aualogous to that described under (0) above, butusing instead of hydrazine, an-equivalent amount of guanidine, acompound having the 'struc-' tural formula I HN=o NH2 NE on;

was obtained with a yield of 89% of theory. Recrystallized frommethanol, the purified product was obtained in the form of colorless,microcrystallineneedle's having a melting point of to 132?v C. v (f)2-CHLORO-G-DIETHYLAMINO-S-PIPERIDYL I- METHYL PURINE I following aprocedure analogous to that described under (a) above, but using insteadof hydrazine, an

having a melting point of 247 to 248 7 equivalent amount ofdiethylamine, a compound having the structural formula was obtained witha yield of 81% of theory. Reprecipitated from cold, about 0.05 Nhydrochloric acid, the purified product was obtained in the form ofcolorless, microcrystalline, elongated, rectangular leaflets having amelting point of 91 to 93 C.

EXAMPLE 3 2,6,8-trimrpholyl purine from 2,6,8-trichl0r0purine andmorpholine A mixture of 1.5 gm. (about 0.005 mol) 2,6,8-trichloropurine,20 cc. morpholine and 0.1 gm. copper sulfate was heated for two hours at200 to 210 C. in a closed tube. The reaction mixture was then taken upin about 100 cc. water. The undissolved portion was separated by vacuumfiltration, yielding 0.9 gm., that is 48% of theory, of a compoundhaving the structural formula For purposes of analysis, the raw productwas recrystallized three times from methanol and then dried at- 60 C.and a pressure of 0.1 kg./cm. The purified product was obtained in theform of colorless needles Analysis.C -;H O N -molecular weight: 375.4.Calculated: C, 54.41%; H, 6.71%; N, 26.11%. Found: C, 55.17%; H, 6.78%;N, 25.83%.

EXAMPLE 4 Preparation of various 2,6,8-triamino-7-methyl purinederivatives from 2-chloro-6,8-diamin0 purines and the the correspondingamines (a) 2-MORPHOLYL-6,8-DI-METHYLAMINO-7-METHYL PURINE A mixture of3.4 gm. (0.015 mol) 2-chloro-6,8-dimethylamino-7-methyl purine, having amelting point of 247 .to 249 C. and obtained from2,6,8-trichlorc-7-methyl clear, weakly yellow reaction solution thusobtained was admixed with about 100 cc. water, whereby a colorless 8crystalline precipitate formed. The precipitate was separated by vacuumfiltration washed and dried at C. 3.5 gm., that is 84% of theory, of acompound having the structural formula r NH CH3 l I N TNH-CH; 1 l, o n

1 4 N were obtained. For purification, the raw product wasreprecipitated once from cold 0.1 N hydrochloric acid. The purifiedproduct was obtained in the form of microcrystalline colorless powder,primarily composed of flat prisms having a melting point of 307 to 309C. (decomposition and brown discoloration).

Analysis.C H ON molecular weight: 277.3. Calculated: C, 51.97%; H,6.91%; N, 35.36%. Found: C, 51.90%; H, 6.96%; N, 35.30%.

(b) 2-MORPHOLYL-6,8-BIS-(DIMETHYLAMINO)-7- METHYL PURINE By following aprocedure analogous to that described under (a) above, but using insteadof 2-chloro-6,8-dimethylamino-7-methyl purine an equivalent amount of2-chloro-6,8-bis-(di-n1ethylamino) 7 methyl purine, a compound havingthe structural formula was obtained with a yield of 84% of theory.Recrystallized from water, the purified product was obtained in the formof a colorless microcrystalline powder (rombohedrons) having a meltingpoint of to 197 C.

(c) 2,6,8-TRIMORPHOLYL-7-METHYL PURINE By following a procedureanalogous to that described under (a) above, but using instead of2-chloro-6,8-dimethylamino-7-methyl purine an equivalent amount of2-chloro-6,8-di-morpholyl-7-methyl purine, a compound having thestructural formula was obtained with a yield of 95% of theory. Afterreprecipitation from a mixture of 0.5 N hydrochloric acid and alcohol(2:1) with ammonia, the purified product was obtained in the form of acolorless, microcrystalline powder having a melting point of 189 to 190C.

(e) 2-PYRROLIDYL-d,S-DIMORPHOLYL-7-METHYL PURINE By following aprocedure analogous to that described under (a) above, but using insteadof 2-ch1oro-6,8-dimethylamino-7-methyl purine and morpholine anequivalent amount of 2-chioro-6,8-dimorpholyl-7 -methyl purine andpyrrolidine, a compound having the structural formula was obtained witha yield of 89% of theory. Upon reprecipitation from 0.1 N hydrochloricacid and drying at 110 C., the purified product was obtained in the formof small, colorless needles having a melting point of 197 to 199 C.

(j) 2-METHYLETHANOLAMINO-6,8-DIMORPHOLYIr7- METHYL PURINE By following aprocedure analogous to that described under (e) above, but using insteadof pyrrolidine an equivalent amount of methyl-ethanolamine, a compoundhaving the structural formula /1 \N N CH:

was obtained with a yield of 64% of theory. Recrystallized from water,the purified product was obtained in the form of a colorless,microcrystalline powder (prisms) having a melting point of l43150 C.

(9) Z-MORPHOLYL-G-HYDRAZINO-8-MORPHOLYL-7- METHYL PURINE By following aprocedure analogous to that described under (a) above, but using insteadof 2-chloro-6,8-dimethylamino-7-methyl purine an equivalent amount of2-chloro-6-hydrazino-8-morpholyl-7 methyl purine, a compound having thestructural formula was obtained with a yield of 42% of theory.Recrystallized from methanol, the purified product was obtained in theform of a virtually colorless, microcrystalline powder (short prisms)having a melting point of 221 to (h) 2- (B-HYDROXYETHYLAMINO-6,8-DIPIPERIDYL- I 7-METHYL PURINE By following a procedure analogousto that described under (Li) above, but using instead of morpholine anequivalent amount of p-hydroxy-ethylamine, a compound having thestructural formula was obtained with a yield of 7 8% of theory.Recrystallized from methanol, the purified product was obtained in theform of very small, colorless prisms having a melting point of 191 to193 C.

EXAMPLE 5 Preparation of various 2,6,8-triamino-7-methyl purinederivatives from 2,6-dichlor0-8-amin0-7-methyl purines and thecorresponding amines (a) 2,6-DIMORPHOLYL-S-PIPERIDYL-7-METHYL PURINE Amixture of 2.9 gm. (0.01 mol) 2,6-dichloro-8- piperidyl-7-methyl purine,having a melting point of 143 to 145 C. and obtained from2,6,8-trichloro-7-methyl purine and piperidine in the presence ofdimethylformamide under'cooling and 10 cc. (0.1 mol) morpholine washeated for about two hours at 200 C. in a closed tube. The raw reactionproduct was immediately reprecipitated from about 1 N hydrochloric acid,separated by vacuum filtration, washed with water, and dried at C. 3.6gm., that is 93% of theory, of a compound having the structural formulawere obtained in the form of a virtually colorless microcrystallinepowder having a melting point of 206 to 208 C. The product thus obtainedwas practically pure, but foranalysis it was once again reprecipitatedfrom very dilute sulfuric acid and recrystallized once from a' mixtureof ethanol and water (1:2). The purified product was thereby obtained inthe form of colorless micro crystalline prisms having a melting point of-209 to 211 C.

Analysis.C H O N mo1ecular weight: 387.5. Calculated: C, 58.89%; H,7.54%. Foundz'C, 59.05%; H, 7.62%.

(b) ae-ntiuonrfioLYL-snNILINo-7-METHYL P'un'rnn By following a procedureanalogous to that described 1 1 under (a) above, but using instead of2,6-dichloro-piperidyl-7-methyl purine an equivalent amount of2,6-dichloro-8-anilino-7-methyl purine, a compound having the structuralformula N on;

N (EH 3 TNHr-OHPQ I N r I I was obtained with a yield of 84% of theory.Reprecipitated from very dilute hydrochloric acid, the purified productwas obtained in the form of a colorless microcrystalline powder having amelting point of 197 to 199 C.

EXAMPLE 6 Preparation of various 2,6-diamino-7-methyl purine derivativesfrom 2,6-dichl0r0-7-methyl purine and the corresponding amines (a)2,6-DIMORPHOLYL-7-METH YL PURINE A mixture of 3.8 gms. (about 0.02 mol)2,6-dichloro- 7-methyl purine and 15 cc. morpholine was heated in aclosed tube for two hours at 200 C. After cooling, the reaction product,a colorless precipitate was rinsed out of the tube with 120 cc. water,filtered on a vacuum filter, the filter cake was washed with water anddried at 110 C. 4.8 gms., that is 84% of theory, of a compound havingthe structural formula N CH3 Analysis. C H O H molecular weight: 304.4.Calculated: C, 55.25%; H, 6.62%.. Found: C, 55.25%;

I (b) 2,6-DIPIPERIDYL7-METHYL PURINE By following a procedure analogousto that described under (a) above, but using instead of morpholine anequivalent amount of piperidine, a compound having the structuralformula was obtained with a yield of 82% of theory. Uponrecrystallization from a mixture of gasoline and benzene (3:1), avirtually colorless, microcrystalline powder (needles) having a meltingpoint of 176 to 178 C. ,was obtained.

EXAMPLE 1 2,6-dim0rph0lyl-8-hydr0xy purine were obtained. Forpurification, the raw product was reprecipitated once from dilute sodiumhydroxide with hydrochloric acid and once from hot dilute hydrochloricacid with ammonia. The colorless powder thus obtained did not exhibitany melting point up to 300 C.

Analysis. C H O N molecular weight: 306.3. Calculated: C, 50.97%; H,5.92%. Found: C, 50.37%; H, 5.98%.

EXAMPLE 8 2-ethylmercapto-6,8-dimorpholyl-7-methyl-purine A mixtureconsisting of a solution of 6.8 gm. (0.02 mol)2-chloro-6,8-dimorpholyl-7-methyl-purine in 33 cc. dioxan and asuspension of sodium ethylmercaptide in dioxan was heated in a closedtube for 45 minutes at 200 C. The sodium ethylmercaptide suspension wasprepared from 15 cc. ethylmercaptan and 0.6 gm. sodium in 15 cc. dioxan.After cooling, the reaction mixture was rinsed out of the tube withabout cc. ethanol and the insoluble portion was separated by vacuumfiltration. The filtrate was then evaporated to dryness. The evaporationresidue was combined With the filter cake. 6.8 gm., that is 93% oftheory, of a compound having the structural formula E j N a N N N O I lB T-SkN N 13 obtained in the form of colorless microcrystalline prismshaving a melting point of 188 to 190 C.

Analysis.--C H O N S-molecular weight: 364.5. Calculated: C, 52.72%; H,6.64%. Found: C, 52.70%; H, 6.64%.

EXAMPLE 9 Z-(B-ethoxy-ethoxy) -6,8 dimorphlyl-7-methyl-purine A mixtureconsisting of 6.8 gm. (0.02 mol) 2-chloro-6,8-dimorpholyl-7-methyl-purine and a solution of 0.5 gm. (0.022 mol)sodium. 75 cc. ethylglycol was refluxed for 1 /2 hours at the boilingpoint. Thereafter, a substantial portion of the alcohol in the mixturewas distilled off and the residue was poured into 250 cc. Water, wherebya virtually colorless precipitate formed. The precipitate was separatedby vacuum filtration, washed, and dried. 4.8 gm, that is 61% of theoryof a compound having the [N/ on;

structural formula were obtained. For purification, the raw product wasrecrystallized twice from a mixture of petroleum ether and benzene(3:1). The purified product was obtained in the form of virtuallycolorless microcrystalline prisms having a melting point of 134 to 136C.

EXAMPLE 1() 2,6,8-trim0rph0lyl-7-methyl-purine (a) A mixture of 4.2 gm.(0.01 mol) 2-chloro-6,8-diiodo-7-methyl-purine and 20 'cc. morpholinewas heated for one hour at 200 C. in a closed tube. The reaction mixturewas then rinsed out of the tube with about 100 cc. water and the aqueoussolution'was allowed to stand for some time. A crystalline precipitateseparated out which was filtered off on a vacuum filter, washed withWater and dried at 110 C. 3.1 gm., that is 79% of theory, of a compoundhaving the structural formula ill were obtained. Uponrepr'ecipitationfrom 0.1 N hydrochloric acid and recrystallization fromwater, the purified product was obtained in the form of colorlessneedles having a melting point of 238 to 240 C.

(b) By repeating the procedure described under (a) above, but using2,6,8-tribromo-7-methyl-purine instead of2-chloro-6,8-diiodo-7-methyl-purine, the same reaction product wasobtained.

EXAMPLE 11 2,6,8-trim0rph0lyl-9-phenyl-purine A mixture of 2.7 gm.(0.009 mol) 2,6,8-trichloro-9- phenyl-purine and 27 cc. morpholine washeated for 1 /2 hours at 160 C. in a closed tube. Thereafter, thereaction mixture was rinsed out of the tube with water, whereby acolorless, amorphous precipitate formed, while the initiallyprecipitated morpholinehydrochloride dissolved.

14 I 2.5 gm., that is 65% of theory of a compound having the structuralformula 2,G-dipiperidyl-8-hydr0xy-9-phenyl-purine A mixture of 2.8 gm.(0.01 mol) 2,6-dichloro-8-hydroxy9-phenyl-purine=and-28 cc; piperidinewas heated for two hours at 160 C. in a closed tube. The reactionmixture was then taken up in water, whereby the reaction productprecipitated as a colorless flocculent precipitate, while the initiallyprecipitated piperidine hydrochloride dissolved. The precipitate wasseparated by vacuum filtration, washed and dried. 2.6 gm., that is 96%of theory, of a compound having the structural formula OH N wereobtained. For analysis, the raw reaction product was recrystallized oncefrom a mixture of ethanol and dioxan (1:1). The purified reactionproduct was a colorless, microcrystailine powder (short prisms) having amelting point of 306 C. At 300 C. it began to turn brown and sintered.

Analysis.-C H ON -molecular weight: 378.5. Calculated: C, 66.64%; H,6.93%. Found: C, 66.90%; H,

6.97%. p EXAMPLE 13 Preparation of various2,6,8-triamino-7-methyl-purine derivativs from2,6,8-Zrichl0ro-7-methyl-purine and the corresponding amines (a)2,6,8-TRIMORPHOLYL-7-METHYL-PURINE A mixture of 2.4 gm. (0.01 mol)2,6,8-triehloro-7-methyl-purine and 25 cc. morpholine (boiling point=128C.) was refluxed at the boiling point for 30 minutes. The

clear solution thus obtained was allowed to cool, whereby V morpholinehydrochloride crystallized out. The reaction mixture was taken up inabout cc. water, whereby the morpholine hydrochloride dissolved, while acrystalline precipitate formed. The crystalline precipitate wasseparated by vacuum filtration, washed and dried. 2.9 gm.,

that is 75% of theory of a compound having the structural formula wereobtained. After reprecipitation from 0.1 N hydrochloric acid andrecrystallization from water the purified reaction product was obtainedin the form of colorless needles having a melting point of 238 to 240 C.

(b) 2,6,S-TRIPIPERIDYL'Z-METHYL-PURINE By following a procedureanalogous to that described under (a) above, but using an equivalentamount of piperidine instead of morpholine and boiling the reactionmixture under reflux for two hours (at about 106 C.), a compound havingthe structural formula was obtained with a yield of 91% of theory. Theraw product was reprecipitated once from about 0.05 N hydrochloric acidand recrystallized once from methanol, yielding the pure product in theform of microcrystalline prisms having a melting point of 216 to 218 C.

EXAMPLE 14 2,'6-dim0rph0 lyl-8-phenyl-purine A mixture of 1.3 gm. (0.05mol) raw 2,6-dichloro-8- phenyl-purine and 30 cc. morpholine wererefluxed at the boiling point for 1 hour. The warm reddish-brownsolution thus obtained was then poured into about 300 cc. Water, wherebyan ivory, amorphous precipitate formed. This precipitate was separatedby vacuum filtration, washed and dried. 1.0 gm., that is 55% of theory,or a compound having the structural formula was obtained. Forpurification, the raw reaction product was reprecipitated once from 0.5N hydrochloric acid and recrystallized once frorn methanol, yieldingcolorless, fine microcrystalline needles having a melting point of 244to 245 C.

Analysis.+C I-I N O -molecular weight: 366.4. Calculated: C, 62.28%; H,6.05%. Found: C, 62.10%; H,

EXAMPLE 15 2,6-dimorphlylyl-8-benzyl-purine By following a procedureanalogous to that described in Example 14, but using 3.8 gm. (0.01 mol)raw 2,6-dichloro-S-benzyl-purine instead of 2,6-dichloro-8-phenyl- 16purine, 2.0 gm., that is 53% of theory, of acompound having thestructural formula m. C i

N TOE:-

I 0 N N were obtained. The raw product was purified by reprecipitatingit once from 0.5 N hydrochloric acid and recrystallizing it once from amixture of methanol and water (2:1), yielding microcrystalline needleshaving a melting point of 223 to 224 C.

Analysis.C l-I N O -molecular weight: 380.5. Calculated: C, 63.15%; H,6.35%. Found: C, 62.95%; H, 6.50%.

EXAMPLE 16 2-phenylmercapt0-6,8-dim0rph0lyl-7-methyl-purine wereobtained. For analysis, the raw reaction product was reprecipitatedtwice from very dilute sulfuric acid and recrystallized twice from about70 cc. methanol. The purified product was a colorless microcrystallineproduct (needles) having a melting point of to 102 C.

Analysis.C H O N Smolecular weight: 412.5. Calculated: C, 58.23%; H,5.87%. Found: C, 57.87%; H, 6.13%.

EXAMPLE 17 Z-phenoxy-6,8-dimorpholyl-7-methyl-purine 6.8 gm. (0.02 mol)2-chloro-6,8-dimorpholyl-7-methylpurine were introduced into a moltenmixture of 15 cc. phenol and 1 gm. sodium hydroxide at 60 C., and theresulting mixture was heated at 200 C. for 10 minutes. The reactionmixture was then taken up in about 250 cc. dilute ammonia, whereby anoily precipitate formed which, however, soon solidified. The precipitatewas separated by vacuum filtration, washed and dried. 6.9 gm., thatis87% of theory, of a compound having the structural formula N fr .10 l II QOWBT N were obtained. The raw product was purified by reprecipitatingit three times'from very dilute sulfuric acid and recrystallizing itonce from methanol, yielding a colorless microcrystalline powder havinga melting point of 192 to 194 C.

Analysis.C H O N molecular weight: 396.4. Calculated: C, 60.59%; H,6.10%. Found: C, 60.82%; H, 6.16%.

EXAMPLE l8 2,6,8-trimorphlyl-9-benzyl-purine 1.0 gm. (0.03 mol)2,6,8-trichloro-9-benzyl-purine, recrystallized from methanol in theform of a colorless, rnicrocrystalline powder (prisms) having a meltingpoint of 126 to 128 C., were heated with cc. morpholine in a closed tubefor 90 minutes at 160 C. After cooling, the reaction mixture was rinsedout of the tube with about 200 cc. 1 N hydrochloric acid, and theresulting suspension was filtered to remove a small amount ofundissolved material. Thereafter, the reaction product was precipitatedfrom the filtrate with 2 N potassium hydroxide. The precipitate wasseparated by vacuum filtration, washed, dried at 105 C. and combinedwith the previous filter cake. 0.8 gm., that is 59% of theory, of acompound having the structural formula EXAMPLE 1 9 Preparation ofvarious 2,6-diamino 8-hydroxy-9-aryl-purine derivatives from2,6-dich'lor0-8r71ydr0xy-9-aryl-' purines and the corresponding aminessolved once in about 15% cold hydrochloric acid and reprecipitated bydiluting the acid solution with water. Subsequently, the reprecipitatedproduct was recrystallized once from a mixture of dioxan and ethanol(221), yielding 0.5 gm., that-is 24% of theory, of an analytically purecompound having the structural formula in the form of colorless,microcrystalline, felted needleschloro-s-hydroxy-(p-chloro-phenyl)-purine, a compound having thestructural formula was obtained with a yield of 32% of theory.Reprecipitated' from about 15% hydrochloric acid by diluting theacidsolution with water, the purified product was obtained in the formof a microcrystalline, colorless substance ,composed of ffilted needleswhich had no melting point up to 350 C.

(.0) 2,fiDIPIPERIDYL-B-HYDROXY-Qr(p-TOLYL)-PURINE By following aprocedure analogous to that described under (a) above, but using insteadof 2,6-di hl9 'p sr hydroxy-9-(p-chloro-phenyl)apurine and morpholyl anequivalent amount of 2,6-dichloro-8-hydroxy-9-(p-tolyly purine andpiperidine, a compound having the structural formula was obtained with ayield of 51% of theory. Reprecipitated from about 15 cold hydrochloricby diluting the acid solution with water, the purified reaction productwas obtained in the form of a virtually colorless, micro,- crystallinepowder having a melting point .of 316 to 318 C.

EXAMPLE 20 Preparation of various 2,6,8-triamin0-7 methyl-purine .de-

rivatives from 2chloro-6,8-diamin0-7-methyl-purines and thecorresponding amines (a) 2,s -DIM0 P o -6r pnurnrL- iqrnrnrn-r'uamu Amixture of 5.0 gm. (0.015 mol) 2-chloro-8-morpho- 19lyl-6-piperidy1-7-methyl-purine, having a melting point of 224 to 226 C.and obtained from 2,6-dich1oro-8-morphoIyLT-methyl-purine having amelting point of 193 to 194 C; and piperidine in acetone by refluxingthe mixture formula at the boiling point, and 20 cc. morpholine wasrefluxed 5 5 V N 7 i at the boiling point for 30 minutes. While thereaction I l N mixture, a clear, yellowish-brown solution, was stillwarm, N N b it was poured into about 100 cc. water, whereby a yellow I JI I crystalline precipitate formed after a short period of time. p N Theprecipitate was separated by vacuum filtration, 10 \lT washed and dried.3.4 gm., that is 58% of theory, of a was obtained with a y fi 0f 32% ofyy compound having the structural formula lized from a mixture ofpetroleum ether and benzene (3:1), the purified product was a colorless,microcrystalline powder having a melting point of 190 to 192 C. (o)2,G-DIPIPERIDYL-S-MORPHOLYL-7-METHYL-PURINE By following a procedureanalogous to that described under (a) above, but using instead of2-ch1oro-6-p1per1dyl- 8-morpholyl-7-methyl-purine and morpholine anequiva- N CH3 lent amount of 2,6-dichloro-8-morpho1y1-7-methyl-pur1neand two molar portionspf piperidine, and refluxing the N N 0 mixture atthe boiling point for 3 hours, a. compound hav- 1 i ing the structuralformula N[ -----N N were obtained. For analysis, the raw reactionproduct N CH; was reprecipitate once from cold 0.1 N hydrochloric acidfl and recrystallized once from a mixture of methanol and N N 0 water(1:3), yielding ivory, microcrystalline prisms hav- I ing a meltingpoint of 207 to 209 C. I N- \N N Analysis.-C H O N molecu1arweight:387.5. Calculated: C 58 89%; H, 754%. Found: C 58 90%; H was obtained wth a yield of 53% of theory. Recrystallized from a mixture of methanoland water 1:1), the 7.68%.

v purified product was obtained 11] the form of colorless, (b) 2.p ppmmyg 3. 7 microcrystalline prisms having a melting point Of 197 t0 PURINE aI The following table llsts additional compounds accord- BY followmg aPYOCedPI'ePBaIOgOUS to that f f ing to the present invention which wereprepared. In addiunder (a) but f d of tion to the name of the reactionproduct, the table shows y 1 3 Y -P alfld morpholine a the reactantsused in preparingthe purine derivative in eqmvalem amount of p y yquestion, the procedure employed, the yield, and the meltpurine andpiperidine, a compound having the structural ing point of the reactionproduct in each case.

. Procedure Yield, Example Compound prepared Starting material Analo-Per- M.P. 0. Remarks gous to cent of example theory number2,6-dipiper1dyl-8-amino-7-methyl-pu-2,6-dichloro-8-amino-7-methyl-purine and 14 97 230-232 rine. piperidine.2,6-dimorpholyl-8- (N-phenyl-piper- 2,6 dichloro 8 (N -phenyl-p1perazino) 7- 5 93 226-228 Reflux azino)-7-methyl-purine.methyl-purine and morpholine. 2-[N-(p-chl0r0phenyl)-piperazine]-6,8-2-chloro-6,8-dimorfiholyl-7-methyl-purine 4 79 227-230 In the presence01' dimorpholyl-7-methyl-purine. and N-(p-chlorop enyl)-piperazine.triethyl-arnine. 2,6 dimorpholyl 8 hexamethylene 2,6-dichloro-8-hexamethyleno-lmiuo-7- 5 159-161- imino-7-methyl-purine.methyl-purine and morpholine. 2-hexamethylene -imino -6,8- dimor-2-ch1oro-6,8-dimorpholy1-7-methy1-purine 4 92 200-202 Reflux for 5hours.

pholyl-7-methyl-purine. and hexamethyleneimine.2-ch1oro-6,8-dimorpholyl-9-(p-tolyl)-2,6,l81-t1richloro-9-(p-tolyD-purine and mor- 1 88 197-198 purine. p 0me. 2,8-dimorpholyl-6-mercapto-7-n1ethyl-2,8-dichloro-6-mereapto-7-methyl-purlne 5 42 255-257 Reflux purine. andmorpholine. 2 -ethoxy 6,8 dipiperidyl 7 -methyl2-chloro-6,8-dipiperidyl-7-methyl-purine and 9 53 134-135 purine. ethylalcohol. 2 dimethylamino -6,8- dimorpholy1-7 2 -ehl0ro6,8-dimorpholyl-7-methyl-purine 4 94 167-169 methyl-purine. anddimethylamine. 2,6,S-trimorpholyl-7-methyl-purine2,6-dichloro-8-morpholy1-7-methyl-purine 14 46 235-237 and morpholine.2,6-dimorpholyl-S-hydroxy-7-methyl-2,6-dichloro-8-hydroxy-7-methyl-purine and 19 81 271-273 purine.morpholine. 2,6dipiperidyl-8-hydroxy-7-methyl-2,6-diehlore-8-hydroxy-7-methyl-purine and 19 82 231-233 purine.piperidjne.

2 morpholyl 6 diethylamino 8 hy 2-chloro-6-dietl1ylam1no-8-hydroxy-7-methyl- 4 57 182-184 (lroxy-7-methyl-purine. purine and morpholine.

2-morgholyl-6-piperidyl-8-hydroxy-7- 2 chloro 6 piperidy1-8-hydroxy -7-methyl- 20 75 248-250 met ylpurine. purine and morpholine.2,6-dimorpholyl-8-ohloro-purine 2,6,8-trichloro-purine and morpholine 172 1 308 2-chloro-6,8-di-(N-phenylpiperazino)-2,6,8-trichloro-7-methy1-purine and N 1 75 About 120 In the presence of7-methyl-purine. phenyl-piperazine. triethylamine. 2 chloro-6-piperidyl-8 -m0rpho1y1- 2, 6 dichloro 8 morpholyl 7 methyl 2 86237-239 Reflux in acetone 7-methyl-purine purine and piperidiue 2 chloro6 morpholyl- 8 (p chloro- 2, 6 dichloro 8 (p chloro aniljno) 7 2 90147-149 anilino)-7-methyl-purine methyl-purine and morpholine2chloro-6,8-dimorpholy1-9-methyl- 2, 6 dichloro 8 morpholyl 9 methyl 281 213-216 purine purine and morpholine2-chloro-6,8-dipiperidyl-9-methyl- 2, 6 dichloro 8 piperidyl 9 methyl 267 162-163 purine purine and piperidine See footnote at end of table.

As previously stated and illustrated in the preceding examples, thetertiary-amines according to the present invention form non-toxic,pharmacologically useful acid addition salts. It is well known in thepharmacological art that the non-toxic acid addition salts of basicpharmacologically active substances do not materially differ from thebasic substances themselves in their pharmacological efiects. The acidaddition salts merely provide a desirable solubility factor. So it iswith the present purine derivatives.

Typical examples of pharmacologically useful non-toxic acid additionsalts of the present purine derivatives are those formed withhydrochloric acid, hydrobromic acid,

sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionicacid, butyric acid, valeric acid, oxalic acid, malonic acid, succinicacid, maleic acid, fumaric acid, lactic acid, tartaric acid, citricacid, malic acid, benzoic acid, phthalic acid, cinnamic acid, salicyclicacid, nicotinic acid, 2-furoic acid and the like. The hydrochlorides,however, have been found to be particularly suitable for practicalpurposes.

The heterocyclic-substituted purine derivatives according to the presentinvention and their water-soluble, nontoxic acid addition salts areuseful pharmacological agents and exhibit pharmacological propertieswhich are difierent from the other known purine derivatives; Moreparticularly, the compounds embraced by Formulas I and Ii above exhibitexcellent coronary dilating properties. 7

To demonstrate that the compounds according to the present inventionhave unexpected and surprising properties in comparison to knowncompounds of related structure, two representative compounds of thegroup disclosed herein were subjected to comparative tests With twoknown heterocyclic-substituted theobromine derivatives for determinationof the relative coronary dilatation activities of the compounds inquestion. The comparative test procedure used was the bubble-flow methoddescribed by Eckenhofl et al. in American Journal of Physiology, vol.148, page 582 (1947). The following table shows the results of thesetests.

Relative value of Compound coronary dilatation activity According toinvention:

2-11ydroxy-fi-methylamino-S-piperidyl-7-methyl-purine 2. 62,6,S-trimorpholyl-7-methyl-purine 6 2,8'dimorpholyl-epiperidylpurine 8Known compounds of related structure:

8 piperazino-thsobrornine (French patent 584,735) '18-piperidyl-theobromine 1.

- The results clearly establish that the representative compoundsaccording to the present invention are distinctly and unexpectedlysuperior to the known compounds in their effectiveness of increasingcoronary blood flow.

Other compounds according to the present invention which exhibit anexcellent coronary dilatation activity are the following given asexamples only:

2,6,8-trimorpholyl-purine 2-rnorpholyl-6,S-dipiperidino-7-rnethylpurine2,6-dirnorpholyl-8-piperidino-7-methylpurine2-chloro-6,8-dimorpholyl-7-methylpurine 2,6-dimorpholyl-7-methylpurine2,6-dirnorpholyl-8-benzylamino-7-methylpurine2-ethylthio-6,8-rlimorpholyl-7-methylpurine2,8-dimorpholyl-6-piperidino-7-methylpurine2,6-dimorpholyl-8-hydroxy-7-methylpurine2(N-methylpiperazino)-6,8-dipiperidino-7-methylpurine 2,G-dimorpholyl-8hexamethyleneimino-7-methylpurine6-(N-methylpiperazino)-2,S-dirnorpholyl-purine2-chloro-6,S-dipiperidino-7-methylpurine2-rnethylethanolamino-6,8-dimorpholyl7-methylpurine2-pyrrolidino-6,8-dirnorpholyl-7-methylpurine2,6,8-tripiperidino-7-methylpurine2,6-dimorpholyl'8-methylbenzylamino-7-methylpurineLmorpholyl-6-diethylamino-8-piperidino-7-methylpurine2,8-dimorpholyl-6-ethoxy-purine 2,S-dirnorpholyh6-amino-purine.2,8-dipiperidino-G-diethanolamino-purine2,6,8-trimorpholyl-9-methylpurineZ-diethanolamino-6,8-dipiperidino-Lmethylpurine In addition toexhibiting coronary dilating properties, the compounds embraced byFormulas I and 11 above possess other important pharmacologicalproperties. For example, 2,6-dimorpholyl-7-rnethyl-purine is eifectiveas a hypotensive agent and respiration stimulant, as well as being fivetimes as effective as a coronary dilatation agent than theophilline.2-morpholyl-6,8-dipiperidyl-7-methylpurine also exhibits excellentanalgesic and sedative properties.2-ethylmercapto-6,8-dimorphclyl-7-methyl-purine is also a very eifectiveanalgesic. 2,6-dimorpho1y1-7- methyl-purine,2-morpholyl-6,8-dipiperidyl-7-methyl-purinerand2,6,8-tripiperidyl-7-rnethyl-purine also exhibit effective antipyreticactivities, and 2,6,8-trimorpholyl 7- methyLpurine also exhibitsantipyretic and sedative properties.2,6-dimorpholyl-8-methy1benzylamino-7-inethylpurine, 2-(N-methylpiperazino) -6,8dipiperidino-7-methylpurine,2-morpholyl-6,8-dipiperidino-7methyl-purine, 2,6-dimorpholyl-8-(N-phenylpiperazyl)-7-methyl-purine, 2- hexamethyleneimino6,8 dimorpholyl-7-methyl puriue,

and 2,6-dipiperidyl-8 morpholyl-7-methyl-purine also-exhibit effectivespasmolytic activities on the intestinal tract.

Finally, 2,6,S-trimorpholyl-purine also exhibits very effectivesedative, antipyretic and analgetic properties.

While we have disclosed certain specific embodiments of the presentinvention, it will be apparent to thoseskilled in the art that theinvention is not limited to these embodiments, and that various changesand modifications can be made without departing from the spirit of theinvention or the scope of the appended claims.

I claim: 7

1. Compounds selected from the group consisting of triandtetra-substituted purines having the structural formula R: 1'1 N N IF En. and p,

substituted N-piperazyl,

one other of substituents R R and R is selected from the groupconsisting of alkyl-amino, di-alkyl-amino, phenyl-amino, benzyl-amino,hydroxy-alkyl-amino, hydroxyalkyl-alkyl-amino, alkylamino-alkyl-amino,hydrazino, guaniclo, hexamethyleneimino, N-piperidyl, N-pyrrolidyl,N-tetrahydropyridyl, N-morpholyl, lower alkyl-substituted N-piperidyl,lower alkylsubstituted N-morpholyl, N'-lower alkyl-substitutedN-piperazyl, N'-phenyl-substituted N-piperphenyl-substituted N-piperazyland N'-halophenylazyl and N'-halophenyl-substituted N-piperazyl and thethird of substituents R R and R is selected from the group consisting ofhalogen, hydroxyl, lower alkoxy, phenoxy, lower alkoxy-substituted loweralkoxy, mercapto, lower alkyl-mercapto, phenylmercapto, amino,alkyl-amino, dialkyl-amino, phenyl-amino, benzyl-amino,hydroxyalkyl-amino, hydroxyalkyl-alkyl-amino, alkylamino-alkylamino,hydrazino, guanido, hexamethyle-neimino, N-piperidyl, N-pyrrolidyl,N-tetrahydropyridyl, N-rnorpholyl, lower alkyl-substituted N-piperidyl,lower alkylsubstituted N-morpholyl, N'-lower alkyl-substitutedN-piperazyl, N'-phenyl-substituted N-piperazyl andN-halophenyl-substituted N-piperazyl, and

R is in addition selected from the group consisting of phenyl,phenyl-substituted lower alkyl and N-morpholyl-substituted lower alkyl,

and their non-toxic, pharmacologically acceptable, watersoluble acidaddition salts.

2. 2,6,8-tri-(N-morpholyl)-purine. 3. 2 (Nmorpholyl)-6,8-di-(N-piperidyl)-7-methyl- 5 purine.

methyl-purine.

References Cited in the file of this patent UNITED STATES PATENTSGoldman et a1 July 22, 1958 UNITED STATES PATENT OFFICE CERTIFICATION OFCORRECTION Patent No. 3,016,378 January 9 1962 Josef Roch It is herebycertified that error appears in the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

- Column 5 line 21, for "morproline" read morpholine lines 68 and 69 for"meltpint" read melting point column 16, lines 35 to 43 the formulashould appear as shown below instead of as in the patent:

[ column 19, line 27, for "reprecipitate read reprecipitated column 21in the table under the heading "Compound prepared'fl, Example 50 shouldread as follows:

2 6-diniorph0lyl-8-benzylmethylamino-7-methylpurine;

same heading Example 86, for "2:6,,8-" read 2 6 8 Signed and sealed this8th day of May 1962.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF TRI- ANDTETRA-SUBSTITUTED PURINES HAVING THE STRUCTURAL FORMULA